X-Message-Number: 17803
From:
Date: Mon, 22 Oct 2001 01:19:44 EDT
Subject: Quality Control and Cryonics
Charles Platt and others have commented about quality control in cryonics and
have referenced my earlier proposals for patient sampling, in particular
brain biopsies of cryopatients. No one has got it quite right (at least from
my point of view) but then it was a long time ago, and, as Charles has noted
a simple matter became contentious. I'll number my points for clarity.
1) Animal research can be remarkably predictive of outcomes in humans if you
are clever, wise, and lucky. Most cancer research has been historically done
with rodents and particularly mice. Countless billions of dollars have been
spent on various models of human cancers in murine (mouse) models. It is now
possible to cure a large number of cancers in mice. However, this did not
proved to be true for humans. Almost all of the money spent since President
Nixon's declaration of a war on cancer in the 1970s was misspent. Animal
rights activists may now take a bow: this stupidity gave you vast and
accurate ammunition against the animal research community.
Monkeys would seem better models to evaluate treatments for head injury and
prolonged cardiac arrest in humans since they are phylogenetically closer to
us than, say, dogs. But the fact is that monkeys are much more resistant to
ischemia than humans. Dogs map humans in terms of timeline, degree and
distribution of neuronal injury more closely than any other animal I have
researched (and I am not alone in this conclusion). They also demonstrate
truly awful behavioral deficits with increasing ischemic times which are
comparable to those observed in humans similarly injured. Sheep and other
grazing animals can suffer devastating neuronal losses with none or very
little change in behavior.
Choosing and validating the right animal model is critical. Even in the
veterinary world there is enormous interspecies difference. The drug you see
advertised on TV for arthritic and elderly dogs (Rimadyl made by Pfizer) does
not work on cats. Similarly, 4-methylpyrazole, a drug which can rescue dogs
from ethylene glycol toxicity is useless in cats.
Closer to the home front, glycerol does not penetrate bovine erythrocytes
significantly below 10 C and several cryoprotectants are impermeant to the
intact rat brain. Rat brains have historically been avoided as models in
cryobiology (perhaps not with justice) because of the extremely dense
neuronal architecture and the idiosyncratic response to cryoprotectants
observed by some scientists in the little work that has been published in
this area.
Scientists engaged in animal research now call this work comparative medicine
and there are staggeringly knowledgeable and prolific Internet lists which
provide both ongoing discourse and a vast reservoir of knowledge to draw upon.
The take home message is that you pick your model and then validate it as
many ways as you can in other relevant systems. This not a criticism of CI or
anyone else. The plans laid out by David Pascal that Yuri Pichugin plans to
follow seem reasonable. Similarly, Charles' concerns about applying research
insights to humans have some merit. You don't really know till you try it,
which brings me to point 2) below:
2) Human cadavers obtained with reasonably short postmortem intervals are
obtainable for about $2,000 each in the greater Los Angeles area. Timing is
the hard part, but if you are a cryonics organization and plan this kind of
work in advance that issue should not be onerous since you should be prepared
for it anyway.
The ethical issues do not trouble me, nor do I think they trouble other
researchers in cryonics. Several of us have already had access to human
brains post mortem which were cryopreserved and subsequently dissected and
examined in some cases. The results were presented at meetings of cryonicists
without objection (i.e., the Lake Tahoe Cryonics meeting in the 1980s and
1990s). If people don't want cryonics but do want to make a contribution by
donating their bodies and brains for irreversible destructive research this
is morally and ethically acceptable. Indeed, acting contrary to this wish
would constitute the assault on the person and the ethically unacceptable
behavior.
To do this kind of work is no different from to work in hospital (as I have)
and to follow a patient's instructions to discontinue dialysis or other life
sustaining treatment even though the quality of life is still high (by my own
standards and those of most of the rest of society). This is done all the
time. To do otherwise constitutes false imprisonment and battery. It also
bespeaks a deep disrespect for the right of the individual to make an
informed choice. Yes, people make bad decisions in this regard. And yes, they
are irreversible. But it is their right to make them and this has been
acknowledged by both social norms and the legal system. Greater evil has
historically come from _imposed_ decisions by governments or individuals who
are not party to all the information or who are driven by ideological or
political agendas.
3) The spinal cord is a good surrogate for the brain, especially as applied
to cryopreservation. Spinal cord samples can be removed from neuropatients
for a variety of evaluations. In the cryopreservation of James Gallagher (a
CryoCare patient) BioPreservation removed a large section of spinal cord and
lumbar nerves. We also removed cryoprotected samples of kidney, liver and
heart. These fairly substantial samples were cooled with the patient at the
same rate and under the same conditions. These samples (which are
CryoCare/BPI property) are, as far as I know, still in the neurocan with the
patient. The purpose of this kind of sample taking was to evaluate by both
freeze substitution electron microscopy and post-thaw electron microscopy how
effective (or damaging) the cryopreservation technique had been.
Unfortunately, my research objectives changed and BPI did not have the money
to pursue this investigation. However, the opportunity still exists and
should be exploited. Had we been better prepared we could have taken a second
set of samples and fixed them immediately following glycerol perfusion and
then examined them under light and electron microscopy. These would have
served as pre-freeze controls for the frozen samples. We were not prepared
for this maneuver (which requires that terminal CPA concentration solution be
made up containing fixative for immediate immersion of the samples after
collection).
4) As to brain biopsies via the burr hole: this was one of the most ludicrous
episodes in the history of cryonics which has had many a ludicrous episode.
The proposal was to take two needle biopsies of non-critical areas of the
cerebral cortex via the burr holes. The amount of biopsied material would
have been equal to about the same volume of tissue contained in a 16 g blood
collection needle (for those of you who have donated blood). A superficial
cortical sample such as this has never caused anyone any detectable
neurological deficit. If you've had as much experience as I have (and other
medically knowledgeable people in cryonics) you would realize that a) this
kind of thing is done every day without problems and b) most patients with
brain tumors (and those around them) do not notice any change in mentation
until the mass is at least the size of a walnut and usually the size of a
golf ball; if not larger. We are not talking about the midbrain here, or the
hippocampus. This procedure was simple, safe and a "no-brainer" as the slang
of the time went.
The tissue would be handled in two ways: One sample would be cooled with the
patient at the same rate and under the same conditions. (Today, if one were
vitrifying the patient the sample could be inserted in a removable capsule in
the esophagus or terminal pharynx to give a worse case cooling rate and then
be removed following cooling.) The other sample would be processed by
immediate post-removal fixation so that the effect of cryoprotective
perfusion could be separated from that of subsequent cryopreservation. While
not perfect, this kind of sampling would return an incredible wealth of
general information and a similar bonanza of information about the quality of
how that particular patient was treated. It is also possible to collect a
sample prior to the start of cryoprotective perfusion to see what condition
the brain is in following legal death and initial cooling and stabilization.
This language is, I believe, already standard in the CI contract.
The issue could have easily been resolved by simply having the client say
"no" if they did not want this procedure done. And, of course, the procedure
would have to be explained in the client's agreement with the cryonics
organization. This did not seem a major obstacle.
Because this practice has not become routine or even occasional, there is
virtually no objectifiable feedback from _any_ cryonics society about what
condition their patients are in. Thus, there is endless and unnecessary
argument that testing could resolve. I did remove cord biopsy samples from
patients frozen by Trans Time in the 1970s and these samples were incredibly
valuable and led to major alterations in practice.
Mike Darwin
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